Process for obtaining (nitroxymethyl)phenyl esters of salicylic acid derivatives

ABSTRACT

A process for obtaining (nitroxymethyl)phenyl esters of salicylic acid derivatives of formula (I) wherein R 1  is the OCOR 3  group characterized in that it comprises the following steps: a) reaction of a halide of a salicylic acid derivative with hydroxybenzylacohol in the presence of a base: b) nutration of the obtained product in anhydrous conditions by a mixture of nitric acid with a different inorganic acid, or an organic acid, or an anhydride of one or two organic acids: c) recovery of the final product.

The present invention relates to a process for obtaining(nitroxymethyl)phenyl esters of salicylic acid derivatives.

It is known in the prior art that the (nitroxymethyl)phenyl esters ofthe salicylic acid derivatives can be prepared by various synthesisprocesses. In the patent application WO 97/16405 the reaction of theacyl chloride of the acetylsalicylic acid with (nitroxymethyl)phenol isdescribed. The (nitroxymethyl)phenol is prepared by a synthesis whichcomprises the following steps:

reaction of the phenol with HBr in organic solvent to obtain(bromomethyl)phenol, and

reaction of the (bromomethyl)phenol in organic solvent with AgNO₃ withformation of (nitroxymethyl)phenol

The process based on the reaction between (nitroxymethyl)phenol and theacyl chloride of the acetylsalicylic acid shows the following drawbacks:

the (bromomethyl)phenol obtained in the first synthesis step is achemically unstable and irritating compound;

the nitrating agent used in the reaction with (bromomethyl)phenol is avery expensive reactant;

the (nitroxymethyl)phenol is an unstable compound, which can easilydecompose in an uncontrollable way; and it must be purified before thereaction with the acetylsalicylic acid chloride, furtherly increasingthe production costs and requiring supplementary units in the productionplant.

In conclusion the synthesis of above derivatives, by using theintermediate (nitroxymethyl)phenol, is difficult and expensive to becarried out on an industrial scale.

In PCT Patent EP 00/00353 in the name of the Applicant a synthesisprocess of nitroxy derivatives of formula (I) (see hereunder) isdescribed, by submitting to nitration with AgNO₃ (hydroxymethyl)phenylesters of the acetylsalicylic acid, obtained by reacting the acidchloride with hydroxybenzaldehyde and reducing the aldehydic group toprimary alcohol. Also this process, as the above mentioned uses silvernitrate as nitrating agent and therefore it is not much advantageousfrom an industrial point of view. Besides the process global yields arenot high.

By using the teaching of the prior art, it is possible to obtain thesalicylic acid nitroxyderivatives of formula (I) (see below) by reactinga (hydroxymethyl)phenyl ester of the acetylsalicylic acid with nitratingreactants based on nitric acid. However under the reaction conditions ofthe prior art the nitric acid produces undesired reactions, such as forexample the nitration of aromatic substrata (ref. “Nitration: Methodsand Mechanism”, 1984 VCH ed., p. 269) and the oxidation of primaryalcohols to aldehydes (ref. “Industrial and Laboratory Nitration” 1976ACS publ., p. 156).

Therefore also said processes of the prior art are unable to solve theproblem of the preparation on industrial scale of the nitroxyderivativesof the salicylic acid as above defined.

The need was felt to prepare nitroxy derivatives of(hydroxymethyl)phenyl esters of the acetylsalicylic acid by a processcheaper than those of the prior art both for the nitrating agent usedand for the yields, and substantially without the drawbacks of the priorart.

An object of the present invention is a process for obtaining(nitroxymethyl)phenyl esters of the salicylic acid derivatives,compounds having the following formula (I):

wherein:

R₁ is the OCOR₃ group; wherein R₃ is methyl, ethyl or linear or branchedC₃-C₅ alkyl, or the residue of a saturated heterocyclic ring having 5 or6 atoms, containing hetero-atoms independently selected between O and N;

R₂ is hydrogen, halogen, linear or branched when possible C₁-C₄ alkyl,linear or branched when possible C₁-C₄ alkoxyl; linear or branched whenpossible C₁-C₄ perfluoroalkyl, for example trifluoromethyl; mono- ordi-(C₁-C₄)alkylamino;

preferably in (I) R₁ is acetoxy and is in ortho position with respect tothe carboxylic group, R₂ is hydrogen; the oxygen of the ester group isbound to the aromatic ring substituted with the (nitroxy)methylene groupin ortho, meta or para position with respect to the (nitroxy)methylenegroup; preferably the position is the meta one;

said process comprising the following steps:

a) reaction of a halide of a salicylic acid derivative of formula (I-A):

 wherein Hal═Cl, Br, and K and R₁ and R₂ have the above indicatedmeaning, with hydroxybenzylalcohol in the presence of a base, in anorganic solvent, or in a mixture of water with a miscible or immiscibleorganic solvent with water, to give the compound (I-B) having thefollowing formula:

 wherein R₁ and R₂ are as above defined;

b) nitration of the compound (I-B) in anhydrous conditions, in an inertorganic solvent, by a mixture formed by steaming nitric acid with aninorganic acid different from nitric acid or with an organic acid, orwith the anhydride of one or two organic acids, to give thenitroxyderivative of formula (I).

c) recovery of the final product by adding water to the organic phase,separating the phases, drying and evaporating the organic phase.

In step a) the base can be an inorganic base, such as for examplehydroxides, oxides, carbonates and bicarbonates of alkaline metals(sodium, potassium, lithium); or an organic base, for example a tertiaryamine, for example aliphatic, cycloaliphatic, heterocyclic, heterocyclicaromatic, such as triethylamina, diisopropyl-ethylamine,N-methylmorpholine, diazaabicyclooctane, etc.

The organic solvent used in step a) can be an organic solvent misciblewith water such as C₁-C₄ aliphatic alcohols, for example methanol,ethanol, isopropanol, n-butanol; or an organic solvent immiscible withwater for example aromatic hydrocarbons such as toluene and xylene,chlorinated organic solvents such as methylene chloride, chlorobenzene,other solvents which can be used are aliphatic esters for example ofC₁-C₄ acids with C₁-C₅ alcohols such as for example ethyl acetate andbutyl acetate, etc.: aliphatic and cycloatiphatic ketones, such asC₃-C₁₂ for example acetone, methylketone, cyclohexanone, etc.

In step a) the reaction is carried out at a temperature in the range−20° C., and +50° C., preferably 0° C.-20° C., by using, with respect tothe hydroxybenzylalcohol moles under reaction, an amount by moles ofacid halide (I-A) in a ratio between 1 and 2, preferably between 1.2 and1.5, and an amount by moles of base between 0.1 and 2, preferablybetween and 2.

The compound I-B) is recovered from the reaction mixture by addition ofwater and optionally, when the reaction takes place in an aqueoussolvent or in a mixture of water with an hydrosoluble organic solvent,by addition of an organic solvent immiscible with water, such as ethylacetate or dichloromethane, the phases are separated, the organic phaseis dried, evaporated and the product is recovered. If necessary, thecompound can be purified by crystallization from solvents such as forexample n-hexane, n-heptane, ligroin, toluene, methanol, isopropanol,diisopropylether, etc or their mixtures. Generally the yields are higherthan 80%.

In step b) the nitration reaction is carried out at a temperature in therange −20° C. and +40° C., preferably from 0° C. to 20° C.; the usedamount by moles of nitric acid is in a ratio between 1 and 6, preferably1 and 3, with respect to the moles of the hydroxyester (I-B); the amountby moles of organic or inorganic acid different from nitric acid, or ofanhydride as above defined, is in a ratio comprised between 0.5 and 6,preferably between 1 and 3 with respect to the moles of the compound(I-B).

The inorganic acid different from nitric acid is for example sulphuricacid; the organic acid is for example methansulphonic acid,trifluoromethansulphonic acid, trifluoroacetic acid, trichloroaceticacid, acetic acid; the organic acid anhydride is for example aceticanhydride, trifluoromethansulphonic anhydride, trifluoroaceticanhydride, trichloroacetic anhydride, etc., or mixed anhydrides such asfor example trifluoroacetic-trifluoromethansulphonic anhydride, etc.

The inert organic solvent used in step b) is a solvent which has boilingpoint lower than 200° C. at atmospheric pressure and it can be achlorinated solvent, such as for example dichloromethane; or anitroalkane such as for example nitromethane, or an aliphatic orcycloaliphatic ether such as for example methylterbutylether,tetrahydrofuran, etc.; an ester for eaample ethyl acetate; or analiphatic or aromatic nitrile such as for example acetonitrile,benzonitrile.

The solvent volume is not critical, generally the volume is comprisedbetwen 1 and 20 times with respect to the amount by weight ofhydroxyester (I-B) under reaction.

When the nitration in step b) is carried out in the presence of anorganic anhydride as above defined, preferably the anhydride is firstmixed with the hydroxyester (I-B) and then the resulting mixture isadded to the nitric acid solution in the inert organic solvent.

Preferably the used organic anhydride is acetic anhydride.

In step c) it is possible to recrystallize the obtained compound byusing solvents such as for example n-hexane, n-heptane, ligroin,methanol, isopropanol or their mixtures.

The following Examples describe the invention without limiting the scopethereof.

EXAMPLE 1a Preparation of 3-Hydroxymethylphenyl Ester of the2-Acetoxybenzoic Acid (Compound I-B) in Admixture Water-organic Solvent

3-hydroxymethylphenol (25.25 g, 0.2 moles) is dissolved in a 5%hydroxide sodium solution (160 ml). To the so obtained solution anacetylsalicylic acid chloride solution (40.4 g, 0.2 moles) indichloromethane (50 ml) is added at roam temperature, under stirring.The mixture is maintained at room temperature under stirring for 2 hoursand then extracted with dichloromethane (2×100 ml). The organic phase isseparated, anhydrified with sodium sulphate and the solvent evaporatedunder vacuum. The residue is crystallized from a mixture of ethylacetate and hexane. 3-hydroxymethylphenyl ester of the 2-acetoxybenzoicacid (45.8 g, 0.16 moles, yield 80%) is obtained.

M.P.: 79°-81° C. ¹H NMR(CDCl₃) δ (ppm): 2.29 (s, 3H); 4.71 (s, 2H);7.07-8.2 (m, aromatics, 8H).

EXAMPLE 1b Preparation of 3-Hydroxymethylphenyl Ester of the2-Acetoxybenzoic Acid (Compound I-B) in Organic Solvent Immiscible WithWater

3-hydroxymethylphenol (10 g, 0.08 moles) is dissolved in toluene (50 ml)containing triethylamine (9.8 g, 0.1 moles). To the so obtained solutionan acetylsalicylic acid chloride solution (16 g, 0.08 moles) in toluene(50 ml) is added at a temperature of 5°-10° C. under stirring. Themixture is maintained at a temperature in the above mentioned range,under stirring for 2 hours, then poured in water and then extracted withdichloromethane (2×100 ml). The organic phase is separated, washed insequence with a 25% w/v potassium carbonate solution, with water, with a3% hydrochloric acid solution and lastly with water again, thenanhydrified with sodium sulphate and the solvent evaporated undervacuum. The residue is crystallized from isopropanol.3-hydroxymethylphenyl ester of the 2-acetoxybenzoic acid (45.8 g, 0.16moles, yield 80%) is obtained.

M.P.: 79°-80° C. ¹H NMR(CDCl₃) δ (pp): 2.29 (s, 3H); 4.71 (s, 2H);7.07-8.2 (m, aromatics, 8H).

EXAMPLE 1c Preparation of 3-Hydroxymethylphenyl Ester of the2-Acetoxybenzoic Acid (Compound I-B) in Organic Solvent Miscible WithWater

3-hydroxymethylphenol (10 g, 0.08 moles) is dissolved in acetone (50ml). In the obtained solution potassium carbonate in powder (22.2 g,0.16 moles) is suspended. To the suspension an acetylsalicylic acidchloride solution (16 g, 0.08 moles) in acetone (50 ml) is added at atemperature of 5°-10° C. under stirring. The mixture is maintained at atemperature in the above mentioned range, under stirring, for 2 hours,then filtered and the solvent evaporated under vacuum. The residue iscrystallized from isopropanol. 3-hydroxymethylphenyl ester of the2-acetoxy-benzoic acid (21.0 g, 0.07 moles, yield 91%) is obtained.

M.P.: 79°-80° C. ¹H NMR(CDCl₃) δ (ppm): 2.29 (s, 3H); 4.71 (s, 2H);7.07-8.2 (m, aromatics, 8H).

EXAMPLE 2 Preparation of 3-Nitroxymethylphenyl Ester of the2-Acetoxybenoic Acid by Nitration With Steaming Nitric Acid, in thePresence of Sulphuric Acid, of 3-Hydroxymethylphenyl Ester of the2-Acetoxybenzoic Acid

A solution of steaming nitric acid (3.92 g, 62.2 mmoles, 3 moles withrespect to the moles of the hydroxyester I-B) and sulphuric acid 96%(6.10 g, 62.2 mmoles, 3 moles with respect to the moles of thehydroxyester 1-B) in dichloromethane (25 ml) is cooled at 0° C. andadded in 1 hour, under stirring and in nitrogen atmosphere, with a3-hydroxymethylphenyl ester solution of the 2-acetoxybenzoic acid (6 g,20.7 mmoles) in 25 ml of dichloromethane. The mixture is then dilutedwith dichloromethane (50 ml) and poured into water and ice (100 g). Theorganic phase is separated, washed with water, anhydrified with sodiumsulphate and the solvent evaporated under vacuum. The residue iscrystallized from isopropanol obtaining the 3-nitroxymethylphenyl esterof the 2-acetoxybenzoic acid (5.6 g, 17 mmoles, yield 82%).

M.P.: 61°-62° C. ¹H NMR(CDCl₃) δ (ppm): 2.31 (s, 3H); 5.44 (s, 2H);7.16-8.22 (m, aromatics, 8H).

EXAMPLES 2a-2f

Example 2 was repeated by varying the moles of nitric acid and ofsulphuric acid with respect to the moles of the intermediate3-hydroxymethylphenyl ester of the 2-acetoxybenzoic acid (I-B). In thefollowing Table 1 the molar ratios of the used reactants with respect tothe compound I-B and the relative per cent ratio between the3-nitroxymethylphenyl ester of the 2-acetoxybenzoic acid (I), the3-(formyl)phenyl ester of the 2-acetoxybenzoic acid (I-B1) are reported,considering, when present, also the starting compound (I-B).

The Table shows that the highest yield is obtained by using the molarratio nitric acid/compound (I-B) equal to 3 and sulphuric acid/compound(I-B) equal to 1.5.

TABLE 1 Relative Ratio Moles Eq. Moles % Example HNO₃/I-B H₂SO₄/I-BH₂SO₄/I-B (I) (I-B) (I-B1) a 2 0 0 5 15 80 b 2 1 0.5 25 0 75 c 1 1 0.554 0 46 d 1 0.5 0.25 5 14 55 e 2 2 1 69 0 31 f 3 3 1.5 99 0 1

EXAMPLE 3 Preparation of 3-Nitroxethylphenil Ester of the2-Acetoxybenzoic Acid by Nitration With Steaming Nitric Acid, in thePresence of Acetic Anhydride, of 3-Hydroxymethylphenyl Ester of the2-Acetoxybenzoic Acid

A solution of steaming nitric acid (1.44 g, 22.8 mmoles), aceticanhydride, (2.33 g, 22.8 mmoles) in dichloromethane (25 ml) is cooled at0° C. and under stirring added in 1 hour, in nitrogen atmosphere, with a3-hydroxymethylphenyl ester solution of the 2-acetoxybenzoic acid (6 g,20.7 mmoles) in 25 ml of dichloromethane. The mixture is heated up to20° C. in one hour and then diluted with dichloromethane (50 ml) andpoured into water and ice (100 g). The organic phase is separated,washed with water, anhydrified with sodium sulphate and the solventevaporated under vacuum. The residue is crystallized from isopropanoland 3-nitroxymethylphenyl ester of the 2-acetoxybenzoic acid (5.6 g, 17mmoles, yield 82%) is obtained.

EXAMPLE 4 Preparation of 3-Nitroxymethylphenyl Ester of the2-Acetoxybenzoic Acid by Nitration With Steaming Nitric Acid, in thePresence of Acetic Anhydride, of 3-Hydroxymethylphenyl Ester of the2-Acetoxybenzoic Acid (Acetic Anhydride Mixed With Hydroxyester)

A solution of steaming nitric acid (1.44 g, 22.8 mmoles), indichloromethane (25 ml) is cooled at 0° C. and added in 1 hour, understirring and in nitrogen atmosphere, with a solution of3-hydroxymethylphenyl ester of the 2-acetoxybenzoic acid (6 g, 20.7mmoles) and acetic anhydride (2.33 g, 22.8 mmoles) in 25 ml ofdichloromethane. The mixture is heated up to 20° C. in one hour and thendiluted with dichloromethane (50 ml) and poured into water and ice (100g). The organic phase is separated, washed with water, anhydrified withsodium shulphate and the solvent evaporated under vacuum. The residue iscrystallized frown isopropanol to give 3-nitroxymethylphenyl ester ofthe 2-acetoxybenzoic acid (6.42 g, 19.5 mmoles, yield 94%).

EXAMPLE 5 Preparation of 3-Nitroxymethylphenyl Ester of the2-Acetoxybenzoic Acid by Nitration With Steaming Nitric Acid, in thePresence of Methansulphonic Acid, of 3-Hydroxymethylphenyl Ester of the2-Acetoxybenzoic Acid

A steaming nitric acid solution (1.44 g, 22.8 mmoles) andmethansulphonic acid (2.55 g, 22.8 mmoles) in dichloromethane (25 ml) iscooled at 0° C. and under stirring added in 1 hour, in nitrogenatmosphere, with a 3-hydroxymethylphenyl ester solution of the2-acetoxybenzoic acid (6 g, 20.7 mmoles) in 25 ml of dichloromethane.The mixture is diluted with dichloromethane (50 ml) and poured intowater and ice (100 g). The organic phase is separated, washed withwater, anhydrified with sodium sulphate and the, solvent evaporatedunder vacuum. The residue is crystallized from isopropanol to give3-nitroxymethylphenyl ester of the 2-acetoxybenzoic acid (2.73 g, 8.29mmoles, yield 40%).

EXAMPLE 6 Preparation of 3-Nitroxymethylphenyl Ester of 2-AcetoxybenzoicAcid by Nitration With Steaming Nitric Acid, in the Presence of AceticAnhydride, of 3-Hydroxymethylphenyl Ester of the 2-Acetoxybenzoic Acid

A steaming nitric acid solution (990 mg, 15.2 mmoles), acetic anhydride(1.55 g, 15.2 mmoles) in dichloromethane (25 ml) is cooled at 0° C. and,under stirring, added in 1 hour, under nitrogen atmosphere, with asolution of 3-hydroxymethylphenyl ester of the 2-acetoxybenzoic acid (4g, 13.8 mmoles) in 25 ml of dichloromethane. The mixture is heated inone hour up to 20° C. and then diluted with dichloromethane (50 ml) andpoured into water and ice (100 g). The organic phase is separated,washed with water, anhydrified with sodium sulphate and the solventevaporated under vacuum. The residue is crystallized from isoprotanol togive 3-nitroxymethylphenyl ester of the 2-acetoxybenzoic acid (4.1 g,12.28 mmoles, yield 89%).

What is claimed is:
 1. A process for obtaining compounds of formula (I):

wherein: R₁ is the OCOR₃ group; wherein R₃ is methyl, ethyl or linear orbranched C₃-C₅ alkyl or saturated heterocyclic ring having 5 atoms,containing heteroatoms independently selected between O and N; R₂ ishydrogen, halogen, linear or branched when possible C₁-C₄ alkyl, linearor branched when possible C₁-C₄ alkoxyl; linear or branched whenpossible C₁-C₄ perfluoroalkyl; mono- or di-(C₁-C₄)alkylamino; saidprocess comprising the following steps: a) reaction between an halideand a salicylic acid derivative formula (I-A)

 wherein Hal═Cl, Br, and R₁ and R₂ have the above indicated meaning,with hydroxybenzylalcohol in the presence of a base in an organicsolvent, or in a mixture of water with an organic solvent miscible orimmiscible in water, to give the compound (I-B) having the followingformula:

 wherein R₁ and R₂ are as above defined; b) nitration of the compound(I-B) in anhydrous conditions, in an inert organic solvent, by a mixtureformed by steaming nitric acid with an inorganic acid different fromnitric acid, or with an organic acid, or with an anhydride of one or twoorganic acids to give the nitroxy derivative formula (I). c) recovery ofthe final product by adding water to the organic phase, separating thephases, drying and evaporating the organic phase.
 2. A process accordingto claim 1, wherein in step a) the base is an inorganic or organic base.3. A process according to claim 1, wherein in step a) the organicsolvents are C₁-C₄ aliphatic alcohols; aromatic hydrocarbons, aliphaticesters, chlorinated organic solvents, aliphatic and cycloaliphaticketones.
 4. A process according to claim 1, wherein in step a) thereaction is carried out at a temperature in the range −20° C. and +50°C. by using, with respect to the hydroxybenzylalcohol moles underreaction, an amount by moles respectively of acid halide (I-A) in therange between 1 and
 2. 5. A process according to claim 1, wherein stepb) nitration is carried out at a temperature in the range −20° C. and+40° C. and the amount by moles of nitric acid is in a ratio between 1and 6, with respect to the moles of the compound (I-B), the amount bymoles of inorganic acid different from nitric acid, or of organic acidor of organic anhydride as above defined, is in a ratio comprisedbetween 0.5 and 6, preferably between 1 and 3 with respect to the molesof the compound (I-B).
 6. A process according to claim 5, whereinnitration is carried out in the presence of an anhydride, which ispremixed with the hydroxyester (I-B) and the resulting mixture added tothe nitric acid solution in the inert organic solvent.
 7. A processaccording to claim 6, wherein anhydride is acetic anhydride.
 8. Aprocess according to claim 1, wherein in formula (I) R₁ is acetoxy andit is in ortho position with respect to the carboxylic group, R₂ ishydrogen; the oxygen of the ester group is bound to the aromatic ringsubstituted with the (nitroxy)methylene group in ortho, meta or paraposition with respect to the (nitroxy)methylene group.
 9. The processaccording to claim 4, wherein the amount by moles of the acid halide isfrom 1.2 and 1.5 and the base between 0.5 and 2.